Paclitaxel (PTX) has a structure represented by the following formula:

Paclitaxel was extracted from the bark of Taxus genus Taxus brevifolia in 1971, which is an active antitumor compound with a unique anticancer mechanism and has definite therapeutic effect on a variety of cancers. Currently in clinical practice, paclitaxel is usually administered by intravenous injection. However, due to its poor water solubility, paclitaxel is usually dissolved in a mixed solvent of polyoxyethylated castor oil (Chremophor EL) and ethanol (1:1, v/v), to prepare paclitaxel injections, which is sold under the trade name “Taxol” or “Paxene”.
Although a great success has been achieved in clinical application, paclitaxel is also restricted by many factors in the meantime: (1) firstly, paclitaxel itself has toxic and side effects, including dose-limiting toxicity and bone marrow suppression (clinically, it is necessary be used in combination with a growth factor for treatment), on normal tissues and cells, and cannot cross the blood-brain barrier, etc; (2) with the use of Chremophor EL, the ensuing problem is serious allergic reactions, primary hyperlipidemia, central nervous system (CNS) toxicity and pharmacokinetics change of paclitaxel [ten Tije A J, et al, Clin Pharmacokinet 42, 655-685, 2003; H. Gelderblom, et al, Eur. J. Cancer 37 (13), 1590-1598, 2001, van Zuylen L, et al, Invest New Drugs 19, 125-141, 2001; R. B. Weiss, et al, J. Clin. Oncol. 8 (7). 1263-1268, 1990]; (3) multiple drug resistance happens due to long-term medication.
In order to solve the aforesaid problems, many scholars at home and abroad have carried out in-depth studies on the structure-activity relationships of paclitaxel, including changing pharmaceutical dosage form, developing a prodrug of paclitaxel, synthesizing taxane derivatives, medication in combination with P-gp inhibitor, and the like. New ways are continuously explored to improve its water solubility, enhance therapeutic effect as well as reduce toxic and side effects.
It has enormous practical significance to carry out studies on the oral taxanes derivatives, since changing the nature of taxanes compounds themselves can fundamentally solve the problems thereof such as poor water-solubility, high toxicity and the like, so as to improve the oral bioavailability, reduce toxic and side effects and enhance therapeutic effect thereof. Furthermore, it will be able to avoid adverse reactions brought by co-solvents, and help prolong therapeutic effect and enhance tolerance of patients by converting injection administration to oral administration.
The researchers found that in the structural modification of paclitaxel molecule, the variation of substituents at C7, C9 and C10 positions have little effect on activity thereof, but these positions are binding sites with P-gp protein. The affinity of paclitaxel molecule with P-gp protein is affected by the size, electrical, hydrogen bond forming ability of the substituents on the positions. Thus, modification on these groups could overcome the multiple drug resistance caused by P-gp over-expression and solve the problem of low oral bioavailability and the like.
In view of this, the inventors were engaged in research of paclitaxel derivatives, and eventually found out a series of novel compounds with improved oral bioavailability. As shown in pharmacological experiments, compared with the prior art, these taxanes derivatives synthesized in the present invention have strong cytotoxicity to a variety of human cancer cell lines and broad-spectrum anti-tumor effects. It can be seen from the in vitro activity data on MCF-7 breast cancer cell line that the cytotoxicity is maintained, while some derivatives even have better cytotoxicity than that of paclitaxel. The in vivo absorption and transport of taxanes derivatives is predicted by using the human-derived colorectal adenocarcinoma cell line Caco-2 cell monolayer model. It can be seen from the experimental results that, compared with the prior art, most of these derivatives have enhanced membrane-permeate absorption capacity and reduced efflux effects, such that they are predicted to have improved oral bioavailability. Therefore, the cytotoxicity of these taxanes derivatives are maintained (or even enhanced), furthermore, their oral bioavailability are also enormously improved.